The nervous system comprises the central and the peripheral nervous system. The peripheral nervous system (CNS) is composed of the brain and spinal cord; the peripheral nervous system (PNS) consists of all of the other neural elements, namely the nerves and ganglia outside of the brain and spinal cord.
Damage to the nervous system may result from a traumatic injury, such as penetrating trauma or blunt trauma, or a disease, disorder or condition, including but not limited to Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, diabetic neuropathy, glaucoma, senile dementia, and ischemia.
Neurodegenerative disorders are commonly associated with ongoing neuronal loss in the CNS. Following the loss of neurons caused by primary risk factors, additional (“secondary”) neuronal loss is mediated by self-compounds, such as glutamate, nitric oxide or reactive oxygen species, that exceed their physiological concentrations. These compounds are implicated in various types of neurological disorders and acute CNS injuries. It is interesting to note that the destructive components common to neurodegenerative diseases have also been identified in autoimmune diseases such as multiple sclerosis; in this disease, myelin damage in the CNS is accompanied by subsequent neuronal loss.
Glaucoma is a slow-progressing optic neuropathy with a high incidence in the elderly population (approximately 1%). Until recently, it was associated with high intraocular pressure (IOP) and therefore attempts have been focused on slowing down the disease progression by anti-hypertensive drugs. Over the years, it became apparent that glaucoma is a family of diseases and not all are associated with pressure. Moreover, it became clear that even when the disease is associated with pressure, the latter may be reduced to normal and even below normal values and degeneration may continue. An ongoing discussion among clinicians has questioned whether the continuous degeneration in glaucomatous patients, in spite of normal IOP values, is a reflection of the existence of additional risk factors besides pressure or a reflection of the increased vulnerability of the remaining neurons and fibers and thus the need to reduce IOP below normal values.
We have suggested in 1996 that the mechanism underlying progressive loss of vision in glaucoma is similar to that occurring in any acute insult to the nervous system or any neurodegenerative disease of the CNS (Schwartz et al, 1996). According to this proposal, in addition to the primary risk factor, e.g. pressure, there is an ongoing process of degeneration that affects neurons that spared the primary event (Schwartz et al, 1996; Schwartz and Yoles, 2000a and 2000b). This process is mediated by compounds that emerged as a result of the primary event or by deficit as a result of the primary risk factor, all of which create a hostile environment to neurons adjacent to the primary insult.
We have further recently observed that under neurodegenerative conditions caused by mechanical (axotomy) or biochemical (glutamate, oxidative stress) insults, the immune system plays a critical role. Thus, it has been found that activated T cells that recognize an antigen of the nervous system (NS) promote nerve regeneration or confer neuroprotection, as described for example in PCT Publication No. WO 99/60021. More specifically, T cells reactive to myelin basic protein (MBP) were shown to be neuroprotective in rat models of partially crushed optic nerve (Moalem et al., 1999) and of spinal cord injury (Hauben et al., 2000). Until recently, it had been thought that the immune system excluded immune cells from participating in nervous system repair. It was quite surprising to discover that NS-specific activated T cells could be used to promote nerve regeneration or to protect nervous system tissue from secondary degeneration which may follow damage caused by injury or disease of the CNS or PNS.
It was further observed by the present inventors that stressful conditions in the CNS harness the adaptive immune response to cope with the stress and that this response is genetically controlled. Thus, the survival rate of retinal ganglion cells (RGCs) in adult mice or rats after crush injury of the optic nerve or intravitreal injection of a toxic dosage of glutamate was shown to be up to two-fold higher in strains that are resistant to CNS autoimmune diseases than in susceptible strains. The difference was found to be attributable to a beneficial autoimmune T cell response that was spontaneously evoked after CNS insult in the resistant, but not in susceptible, strains. Thus, the survival rate of neurons as a result of such an insult is higher when T cell response directed against self is evoked, provided that it is well-regulated. In other words, it was demonstrated that a protective autoimmune response is evoked to oppose the stressful conditions so as to protect the animal from the insult consequences. It was further observed that in animals with an impaired ability to regulate such a response, or in animals devoid of mature T cells (as a result of having undergone thymectomy at birth), the ability to cope with the stressful conditions is reduced. Consequently, the survival rate of neurons following CNS insult in these animals is significantly lower than in animals endowed with an effective mechanism for mounting protective autoimmune T cell-mediated response (Kipnis et al., 2001).
More recent studies in our laboratory have shown that autoimmune neuroprotection is the body's physiological defense mechanism awakened when CNS injury occurs (Kipnis et al., 2001; Yoles et al., 2001). We demonstrated that resistance to increased IOP differs among strains (Bakalash et al., 2002) and that this difference is linked to the ability to harness an autoimmune response with a beneficial outcome. We further showed that in the absence of mature T cells (through neonatal thymectomy), the relative resistance to IOP elevation loses its beneficial trait, and vice versa, when splenocytes from a resistant strain are passively transferred to an MHC-matched susceptible strain, the neuroprotective effect is resumed (Bakalash et al., 2002). It was further shown by our group that passive vaccination with T cells is also effective in acute injuries such as partial optic nerve crush or spinal cord contusion (Kipnis et al., 2001; Moalem et al., 1999).
Attempting to boost such an anti-self response as a way of protecting neurons from insulting conditions has revealed that the vaccinating antigen should be derived from compounds residing in the site of the lesion. Thus, the use of the self-antigen derived from interphotoreceptor binding protein (IRBP), the most abundant peptide in the eye (Bakalash et al., 2002; Mizrahi et al., 2002), resulted in RGC protection in both susceptible and resistant strains. In contrast, the use of peptides derived from compounds residing in the myelin associated with the optic nerve led to no benefit to the retinal ganglion cells suffering from IOP elevated insult.
Trying to design a vaccination for glaucoma that will boost the immune system without risk of evoking an autoimmune disease, we chose to focus on Copolymer 1, and have shown that it is neuroprotective for glaucoma when given with an adjuvant (Bakalash et al., 2002; Schori et al., 2001; Schwartz and Kipnis, 2002; WO 01/52878; WO 01/93893). Cop-1 immunologically cross-reacts with a wide variety of self-reactive T cells. Accordingly, its activity is reminiscent of that of altered peptide ligand, a self-peptide that has been altered and has lost pathogenicity as a result (WO 02/055010; Kipnis and Schwartz, 2002).
Copolymer 1, also called Cop 1 or glatiramer acetate, is a non-pathogenic synthetic random copolymer composed of the four amino acids: L-Glu, L-Lys, L-Ala, and L-Tyr, with an average molecular fraction of 0.141, 0.338, 0.427, and 0.095, respectively, and an average molecular weight of 4,700-11,000. COPAXONE® (a trademark of Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel), the brand name for glatiramer acetate, is currently an approved drug in many countries for the treatment of multiple sclerosis. It is very well tolerated with only minor adversary reactions. Although treatment with Cop 1 by ingestion or inhalation is disclosed in U.S. Pat. No. 6,214,791, the sole route of administration of Cop 1 to multiple sclerosis patients is by daily subcutaneous injection.
Recently it was found that in animal models Cop 1 provides a beneficial effect for several additional disorders. Thus, Cop 1 suppresses the immune rejection manifested in graft-versus-host disease (GVHD) in case of bone marrow transplantation (Schlegel et al., 1996; U.S. Pat. No. 5,858,964), as well as in graft rejection in case of solid organ transplantation (Aharoni et al., 2001). Cop 1 and Cop 1-related copolymers and peptides have been disclosed in WO 00/05250 for treating autoimmune diseases.
WO 01/52878 and WO 01/93893 of the present applicants disclose that Cop 1, Cop 1-related peptides and polypeptides and T cells activated therewith protect CNS cells from glutamate toxicity and prevent or inhibit neuronal degeneration or promote nerve regeneration in the CNS and PNS. WO 01/93828 discloses that Cop 1 can be used for treatment of CNS disorders. None of these publications discloses immunization by administration of eye-drops containing Cop 1.
Poultry vaccines for administration as eye drops comprising a live virus or recombinant DNA coding for immunogenic proteins from infectious agents have been described for prevention of viral diseases in avian animals (Mukibi-Muka et al., 1984; Sharma, 1999; Russell and Mackie, 2001).
Citation or identification of any reference in this section or any other part of this application shall not be construed as an admission that such reference is available as prior art to the invention.